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J Comput Chem. 2015 Jul 30;36(20):1536-49. doi: 10.1002/jcc.23964. Epub 2015 Jun 12.

Accelerated molecular dynamics simulations of protein folding.

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Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California.
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California.
Department of Pharmacology, University of California at San Diego, La Jolla, California.


Folding of four fast-folding proteins, including chignolin, Trp-cage, villin headpiece and WW domain, was simulated via accelerated molecular dynamics (aMD). In comparison with hundred-of-microsecond timescale conventional molecular dynamics (cMD) simulations performed on the Anton supercomputer, aMD captured complete folding of the four proteins in significantly shorter simulation time. The folded protein conformations were found within 0.2-2.1 Å of the native NMR or X-ray crystal structures. Free energy profiles calculated through improved reweighting of the aMD simulations using cumulant expansion to the second-order are in good agreement with those obtained from cMD simulations. This allows us to identify distinct conformational states (e.g., unfolded and intermediate) other than the native structure and the protein folding energy barriers. Detailed analysis of protein secondary structures and local key residue interactions provided important insights into the protein folding pathways. Furthermore, the selections of force fields and aMD simulation parameters are discussed in detail. Our work shows usefulness and accuracy of aMD in studying protein folding, providing basic references in using aMD in future protein-folding studies.


accelerated molecular dynamics; enhanced sampling; free energy; protein folding; reweighting

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